Extremely flexible plaster acting dermally or transdermally, and method for producing same

ABSTRACT

A process for the production of an extremely flexible patch having a dermal or transdermal action and having an adhesive matrix layer which comprises the active compound and is provided with a detachable protective layer on a side facing the skin is characterized in that the matrix layer is not covered on the side facing away from the skin but is given a non-adhesive treatment on its open surface.

The present invention relates to an extremely flexible patch having adermal or transdermal action for controlled release of active compoundsto human or animal skin, which comprises an adhesive matrix layer whichcontains the active compound or compounds and has been freed from itsadhesive properties on the side facing away from the skin, and to aprocess for its production.

Patches for controlled release of active compounds to human or animalskin are adequately known and described as transdermal therapeuticsystems (TTS) or “transdermal delivery systems” (TDS). A distinction isgenerally made in these systems between so-called pouch or reservoirpatches and so-called matrix patches, depending on the structure and thenature of the release of active compound. In the first case, suchpatches comprise a flat pouch or sachet which contains the activecompound and of which the side facing away from the skin is impermeableand the side facing the skin is constructed as a control membrane coatedwith an adhesive for the purpose of adhesion to the skin. Because oftheir complicated structure, the production of such patches is veryexpensive, since the individual components have to be preparedseparately and then brought together into one system.

Furthermore, because of the necessary thickness of the patch, thewearing properties are impaired. Moreover, with the pouch system thereis the risk of so-called “drug dumping”, that is to say sudden completerelease of the active compound to the skin owing to destruction of themembrane or of the pouch. EP 0 235 563 describes, for example, atransdermal therapeutic system or patch of this type for combinedadministration of oestrogens and gestagens.

Systems or therapeutic patches which comprise the active compound inmicroencapsulated form in the reservoir are known from U.S. Pat. No.4,624,665. The reservoir is embedded between a backing layer and amembrane. The peripheral edge of the patch is provided with a contactadhesive. The structure and the production of such patches are verycomplicated, since the active compound has to be microencapsulated anddistributed homogeneously, to then be embedded between the backing layerand membrane. Furthermore, the patch must be provided with an edge whichsticks to skin and covered with a protective layer. Matrix systems orpatches generally comprise a backing layer which faces away from theskin and is impermeable to the active compound and an adhesive layer inwhich the active compound is distributed. To protect the adhesive layer,this is provided with a protective film which has been given an abhesivetreatment and must be removed before application. DE-OS 20 06 969, forexample, describes such a system in which contraceptive substances areincorporated into the adhesive components or the adhesive film. Thisspecification shows that the adhesive film can be an acrylate.

A disadvantage of known pouch, reservoir or matrix systems or patches isthe necessary thickness caused by the production process, which impairsthe flexibility in an undesirable manner. The flexibility of the systemor patch in fact has a direct effect on its wearing properties, sincethe wearing comfort required increases with decreasing thickness anddecreases with increasing thickness.

The present invention is based on the object of providing a process forthe production of an extremely flexible patch which has a dermal ortransdermal action, is provided with preferred wearing comfort,dispenses entirely with a separate backing layer and consequently isthinner and more flexible and, as a result of reduced expenditure duringproduction, results in a less expensive alternative to the systems todate.

This object is achieved by a process according to the features of themain claim.

Surprisingly, it has been found that as a result of their greatersuppleness, such patches also adhere to skin more reliably and for alonger time.

Because of the-comparatively lower thickness and higher flexibility, incontrast to conventional systems or patches the patch according to theinvention is also suitable for permanent application to difficult areasof the body, e.g. in the region of the ear, in the genital region or ontoenails and fingernails.

A preferred embodiment of a patch according to the invention, given byway of example, is constructed as follows: it comprises a supportinglayer, an adhesive part with a non-adhesive surface of a matrixcontaining the active compound and a detachable protective layer.

To apply the patch according to the invention, the protective layer isremoved and the patch is applied to the application area with the aid ofthe supporting layer such that the adhesive side is facing the skin, andthe supporting layer is then peeled off from the side which has beengiven a non-adhesive treatment.

To cancel the adhesive strength on the surface of adhesive layers,suitable methods are all those which modify the surface structure

a) by changing the molecular bond of the adhesive system in the surfaceitself

1. by changing the state of aggregation—liquid/crystalline (influence ofheat)

liquid=adhesive

crystalline=non-adhesive,

2. by crosslinking, chemically by crosslinking agents or by radiation,the parts of the polymer molecules which determine the adhesivestrength,

b) by changing the surface structure by means of additives which providea new interface on the outside, are available, additives which can beused being:

1. solid particles with a particle size in the range of 0.5-20 μm, whichare either spherical or platelet-like in structure. Starch flours orlaminar silicates, such as bentonite or mica, may be mentioned as anexample. The pulverulent nature of these particles, which allow auniform application, is decisive.

2. liquid media which, after application,

a) form a liquid, semi-solid or solid film physically by themselves—(for example silicone oil, fats, aqueous acrylate dispersions orpolymer solutions),

b) form a new interface by chemical cross-linking.

The adhesive matrix layer can comprise polymers, such ashydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymer 60:40,ethylcellulose, acrylic and methacrylic acid ester copolymers withtrimethylammoniummethyl acrylate, copolymers of dimethylaminomethacrylicacid and neutral methacrylic acid esters, shellac, cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate, polymers ofmethacrylic acid and methacrylic acid esters, ethyl acrylate/methylmethacrylate copolymer 70:30, methacrylic acid/methyl acrylate copolymer50:50, gelatin, polyvinyl acetate, methacrylate, acrylate dispersions,polyether/polyamide block copolymers, polyethylene/methyl methacrylateblock copolymers, polyurethanes, polyester block copolymers,polyisobutylene/styrene/styrene copolymer,styrene/butadiene/styrene/isoprene copolymer, ethylene/vinyl acetatecopolymer, polyamide, nitrocellulose and further coat- or film-formingagents which are known to the expert and have at least one reactivepolymer end group. The addition of plasticizers results automatically inaccordance with the proviso of the required flexibility of the film.

Further substances which may be added or applied to complete a film tobe crosslinked are: acrylic- and/or methacrylic-modified polysiloxaneswhich have a high content of non-polar methyl groups and contain atleast one reactive terminal acrylic and/or methacrylic acid group, andfurthermore mono-, bi- and trifunctional acrylic and methacrylic acidesters. Vinyl or epoxide compounds containing perfluoroalkyl orperfluoroalkenyl groups or epoxypropylsiloxanes are moreover possible.

Suitable pulverulent substances are additives, in particular, of SiO₂,zinc stearate, mica, bismuth oxychloride, titanium dioxide, magnesiumoxide, talc, magnesium stearate and other metal salts of fatty acids,and furthermore triglycerides and the colored pigments used inparticular in decorative cosmetics. In this connection, it should benoted that the surface of the adhesive matrix layer containing theactive compound which faces away from the skin can also be deactivated,for example, by the abovementioned pulverulent foreign substances afterapplication to the skin.

The term “active compound” in connection with the present invention isunderstood as meaning organic and inorganic chemical substances whichcan migrate out of the constituents containing them in the deviceaccording to the invention and as a result cause a required therapeuticor cosmetic effect. Among the fields of use of the patch according tothe invention, human and veterinary medicine and use on plants are ofparticular importance.

The active compounds to be released are preferably used for dermaltreatment of local skin diseases, intra- and transdermal treatment ofdiseases and wound treatment or skin care in cosmetic formulations.

Local anaesthetics, local antibiotics, antiseptics, antimycotics,antihistamines and antipruritic medicaments, keratolytic agents andcauterizing medicaments, virustatics, antiscabies agents, steroids andvarious substances for treatment of acne, psoriasis, photodermatitis orprecancerous stages are used for dermal treatment of local skindiseases. The active compounds which are administered intradermallyinclude, for example, steroid and non-steroid antirheumatics, localanaesthetics, circulation-promoting substances or vasoprotectors andvasoconstrictors for treatment of vascular diseases, and activecompounds for influencing processes in the subcutaneous fatty tissue.Active compounds administered transdermally include, for example,analgesics, antiarrhythmics, narcotics and antagonists thereof,neuroleptics, hormones and hormone replacement substances,antidepressants, tranquillizers, hyponotic agents, psychostimulants,anti-Parkinson agents, ganglion blockers, sympathomimetics,alpha-sympatholytics, beta-sympatholytics, antisympathotonics,antiasthmatics, antiemetics, appetite depressants, diuretics or activecompounds for reducing weight and the like.

Preferred active compounds are steroids, such as oestradiol, oestriol,progesterone, norethisterone, norethindrone, levonorgastrel andits-derivatives and ethynodiol diacetate, norgestamate, gestadene,desogestrel, demegestrone, promegestrone, testosterone, hydrocortisoneand derivatives thereof; nitro compounds, such as amyl nitrate,nitroglycerine and isosorbide dinitrate; amine compounds, such asnicotine, chlorpheniramine, terfenadine and triprolidine; oxicamderivatives, such as piroxicam; mucopolysaccharidases, such asthiomucase; opiodes, such as buprenorphine, morphine, fentanyl andsalts, derivatives or analogues thereof, naloxone, codeine,dihydroergotamine, lysergic acid derivatives, pizotyline, salbutamol andterbutaline; prostaglandins, such as those of the PGA, PGB, PGE and PGFseries, such as misoprostol and enprostil, omeprazole and imipramine;benzamides, such as metoclopramine and scopolamine; peptides and growthfactors, such as EGF, TGF, PDGF and the like; somatostatin; clonidine;dihydropyridines, such as nifedipine, nitrendipine, verapamil,diltiazem, ephedrine, propranolol, metoprolol and spironolactone; andthiazides, such as hydrochlorothiazide and flunarizine. For woundtreatment, haemostatic active compounds and wound-cleaning substances,such as, for example, enzymes, antiseptics, disinfectants andantibiotics, analgesic agents and anaesthetizing active compounds andwound healing-promoting active compounds for stimulating granulation,for inducing vascularization or for promoting epithelialization areemployed.

On the other hand, the patch can also be employed for wound treatmentfor release of oestradiol on chronic wounds, for example ulcera cruris.

In a preferred embodiment for intradermal administration of activecompounds, the adhesive layer comprises a eutectic mixture of the localanaesthetics lidocaine and prilocaine. By means of this mixture ofactive compounds, both for intradermal analgesia before, for example,vein puncture and for treatment of rheumatoid arthritis, an action canbe achieved which cannot be achieved with the active compounds andactive compound combinations usually employed from the group of topicalanaesthetics.

In another preferred embodiment of the patch according to the invention,the film layer comprises plant formulations, such as, for example,extracts or tinctures. These can be used for treatment of local skindiseases, such as, for example, oak bark extract, walnut extract, arnicaflower tincture, hamamelis bark extract, ribwort extract, pansy extractor thyme or sage extract, for treatment of damaged and injured skin,such as, for example, St John's wort tincture, sunhat tincture, camomileflower extract or marigold flower tincture, and for care of stressed anddamaged skin; such as, for example, birch leaf extract, stinging nettleextract, coltsfoot extract, comfrey tincture, horsetail extract or aloevera extract. However, plant formulations can also be released from thefilm layer for intradermal treatment of diseases, such as, for veinconditions, or arnica, marigold and capsicum extracts and tinctures forcontusions, sprains or bruises. Plant formulations in the systemaccording to the invention, however, can also be employed in transdermaltreatment, thus, for example, ginseng extract for geriatric complaints,valerian tincture, melissa and hop extract for calming in cases ofoverexcitation, sleep disturbances and stress, cola and tea extracts forachieving a stimulating action or hawthorn extract for stabilizing thecirculation.

Another particular embodiment relates to the use of the patch accordingto the invention as a carrier of narcotics, psychotropic drugs andagents for treatment of Alzheimer's disease and senile dementia. Thesehighly potent medicaments require a system with guaranteed wearingproperties for several days.

The following example serves to illustrate a production of a patchaccording to the invention.

The solution of an adhesive composition containing active compound andcomprising

Active compound 5.0 g Methacrylic acid copolymer 5.0 g Dimethylphthalate 0.25 g Ethyl acetate 79.75 g

is applied to a siliconized polyester film 100 μm thick (protectivelayer) and dried at about 80° C. After the drying operation, theresulting laminate passes through a spray tunnel in which magnesiumstearate powder is sprayed onto the surface of the adhesive layer(matrix). Magnesium stearate powder which does not adhere to the surfaceof the matrix layer is removed by a polishing roll.

The matrix surface treated in this way is covered by a siliconizedpolyester film 30 μm thick (supporting layer).

Transdermal therapeutic patches are stamped out, by known processes,from this laminate which is obtained in this way and comprisesprotective layer, polymer matrix sprayed with powder and supportinglayer.

What is claimed is:
 1. An active compound delivering patch formed by apressure-sensitive adhesive matrix layer containing a pharmacenticallyactive compound for controlled release through an adhesive contactsurface of said matrix layer, said adhesive contact surface beingcovered by a removable protective layer wherein the matrix layer surfacefacing away from said adhesive contact surface has a non-adhesiveproperty to eliminate the need for a backing layer, without changing thecharacter of the matrix itself.
 2. The active compound delivering patchof claim 1 further comprising a removable supporting layer on the sidefacing away from the adhesive contact surface.
 3. The active compounddelivering patch of claim 1 having a matrix layer having a thickness toprovide high flexibility to said active compound delivering patch.